Arsenic poses a serious environmental threat to human health. It contaminates numerous water supplies nationwide, from natural or industrial sources, and can be found in our food supply. Complicating this picture is the occurrence in many contaminated sources of additional metals such as copper, manganese, lead, zinc, and cadmium, each with a link to human health problems. Specific progress has been made recently in the development of transgenic animal models of arsenic carcinogenesis. These models function to recapitulate tumor formation when challenged with arsenic or other carcinogens in a controlled laboratory setting. This study aims to address the molecular and cellular changes taking place in a transgenic murine model of arsenic carcinogenicity, the Tg.AC mouse. This model will allow us to determine if there is toxic synergy, anergy, or additive effects following chronic administration of arsenic and other metals. We will study molecular and cellular responses to individual metal(loids) or mixtures using high-density cDNA microarrays, as well as any morphological changes, Our hypothesis is that the relative risk to human health from complex mixtures of metal(Ioid)s can be predicted based on an improved understanding of the molecular and cellular events taking place in a mammalian model of tumor formation. For the proposed grant period we propose the following specific aims.(1) to assess the reproducible gene expression changes during chronic metal(Ioid) mixture administration in five tissues of the Tg.AC mouse model that have particular human disease relevance: lung, bladder, blood, liver, and skin. Our hypothesis is that there exist tissue-specific and metal-specific expression signatures, and that novel signatures will be attainable for mixtures, suggesting mechanisms by which these mixtures interact to increase or decrease tumorigenicity. (2) to assess the carcinogenic potential of complex mixtures of metal(Ioid)s in the Tg.AC transgenic mouse model. Our hypothesis is that mixed metal(Ioid)s will affect the number and severity of tumors induced through synergistic, antagonistic, or additive mechanisms. Our understanding of these mechanisms will be generated from gene expression results in specific aim 1. Tissue at the site of tumors, as well as from other organs, will also be examined for pathological changes reflective of carcinogenesis.